Treatment of Immune Related Adverse Events With CD24Fc (TIRAEC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 3
- 试验地点
- 2
- 主要终点
- Number of Participants With New Adverse Event (AE) of Grade >= 3 (Phase I)
研究概览
简要总结
This phase I/II trial investigates the side effects and how well CD24Fc works in treating immune related adverse events in patients with solid tumors that have spread to other places in the body (advanced). CD24Fc may prevent autoimmune reactions due to the tissue damage induced by cancer treatment. CD24Fc binds to injured cell components and prevents inflammatory responses. CD24Fc also acts to turn off the immune system after it has been activated ("immune checkpoint"). Adding CD24Fc to standard treatment may shorten the recovery time and reduce the severity of side effects from immunotherapy.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein CD24Fc (CD24Fc) in patients with advanced solid tumors who developed debilitating immune-related adverse events (irAEs) from immune check point inhibitors (ICIs). (Phase I) II. To determine if CD24Fc shortens the recovery time of irAE and increases the recovery rate of irAE in cancer patients with grade (G)2 or 3 irAEs. (Randomized phase II)
SECONDARY OBJECTIVES:
I. Time to irAE reduction by at least 1 grade. (Phase I) II. Time to all irAEs reduced to grade =< 1. (Phase I) III. Time to resume ICI treatment. (Phase I) IV. Recovery rate (as defined by reduction of irAE by one grade) at day (D)42. (Phase I) V. To estimate the time to all irAEs reduced to =< 1. (Randomized phase II) VI. To record the use of steroids (drug, dose, duration) and other treatment for irAE. (Randomized phase II) VII. To record the time to resume ICI treatment. (Randomized phase II) VIII. To estimate the preliminary overall response rate (ORR), progression free survival (PFS), and 1-year overall survival (OS) after treatment with or without CD24Fc. (Randomized phase II) IX. To determine if CD24Fc treatment changes the levels of inflammatory markers in the plasma. (Randomized phase II)
OUTLINE:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability to understand and willingness to sign an informed consent form
- •At least 18 years of age
- •Histologically confirmed advanced solid tumors
- •Patients must have grade 2 or 3 irAEs from at least one ICI-containing regimen. Both newly emerging and persistent irAEs are allowed. Systemic steroid therapy or any other form of immunosuppressive therapy for irAEs is allowed. The specific irAEs are
- •Grade 2-3 diarrhea/colitis: Patients with >= 4 stools per day or moderate-severe increase in ostomy output compared to baseline but not life-threatening diarrhea
- •Grade 2-3 pneumonitis: Mild to moderate (grade 2) or severe (grade 3) symptoms (including hypoxia, shortness of breath, requiring oxygen) but not life-threatening respiratory compromise requiring urgent intervention (e.g., tracheostomy or intubation)
- •Grade 2-3 renal irAE: Creatine increased between 1.6-6.0 x upper limit of normal (ULN) or =< 3.0 x baseline if baseline was abnormal, estimated glomerular filtration rate (eGFR) or creatinine clearance >= 15 ml/min/1.73m^2 but not life-threatening consequences or requiring dialysis
- •Grade 2-3 Hepatic irAE: AST/ALT/ALP levels 3-20 x ULN, and T bilirubin increased <5 x ULN
- •Grade 2-3 skin rash: moderate (10-30% body surface area, BSA) to severe (> 30% BSA) but not life-threatening skin lesions or Stevens-Johnson syndrome
- •Eastern Cooperative Oncology Group (ECOG) performance status < 2
- •Life expectancy of >= 3 months at the time of enrollment
- •Pretreatment absolute neutrophil count (ANC) >= 1,000/uL obtained within 14 days prior to 1st dose of treatment
- •Pretreatment hemoglobin >= 8 gm/dL obtained within 14 days prior to 1st dose of treatment
- •Pretreatment platelet count of >= 75,000/uL obtained within 14 days prior to 1st dose of treatment
- •Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Or, female subjects of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first study drug administration
- •Male and female subjects who agree to use highly effective method of birth control (e.g., implants, injectables, birth control pills with two hormones, intrauterine devices [IUDs], complete abstinence or sterilized partner, and female sterilization) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug
排除标准
- •Prior CD24Fc therapy
- •Any known active hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, including patients who have an active infection requiring systemic therapy. History of COVID-19 or known asymptomatic carrier of SARS-CoV-2 virus is allowed
- •Pregnant or lactating women
- •Any medical condition including additional laboratory abnormalities, or psychiatric illness that would, in the opinion of the investigator, prevent the subject from participating and adhering to study related procedures
- •Any known severe bacterial, fungal, or viral infection that in the opinion of the investigator would interfere with patient safety or compliance on trial within 2 weeks prior to enrollment
- •Patients with concomitant proarrhythmic medications
- •Patients with heart failure in New York (NY) Heart Association stage IV
- •Any grade 4 irAE symptoms and Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade 4 toxicity
- •AST, ALT, gamma glutamyl transpeptidase (GGT), or ALP > 20.0 x ULN regardless of baseline
- •Blood bilirubin >5.0 x ULN regardless of baseline
- •Creatinine > 6.0 x ULN or creatinine clearance <15 ml/min/1.73m2
- •Urine: Anuria < 140 ml in 24 hours
- •Electrolytes hyponatremia, sodium < 120 mmol/L
- •Hypokalemia, potassium < 2.5 mmol/L
- •Creatine kinase (CPK) > 10.0 ULN
- •Electrocardiogram (ECG): Prolonged QT interval >= 480 mS, corrected by Fridericia's formula. Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrythmia
研究组 & 干预措施
Phase I (CD24Fc)
Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 with standard of care (i.e., steroids per treating physician and best supportive care) in the absence of disease progression or unacceptable toxicity.
干预措施: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc (Biological)
Phase II, Arm II (placebo)
Patients receive placebo IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.
干预措施: Placebo Administration (Drug)
Phase II, Arm I (CD24Fc)
Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.
干预措施: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc (Biological)
结局指标
主要结局
Number of Participants With New Adverse Event (AE) of Grade >= 3 (Phase I)
时间窗: At day 60
Number of Participants with New Adverse Event (AE) of Grade \>= 3 (Phase I)
Time to Recovery From Grade 2 or 3 irAE (Phase II)
时间窗: Up to 1 year
Will assess time to recovery from grade 2 or 3 irAE (as defined by reduction of at least 1 grade in irAE severity) from the initiation of CD24Fc treatment. Patients who have not been documented to have event (reduction of at least 1 grade) will be censored at the date of the latest clinical assessment that documented as being free of event.
Recovery Rate (Phase II)
时间窗: At day 42
Defined by reduction of irAE by one grade. Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians and associated 95% confidence intervals will be calculated, and comparisons between groups will be performed by log-rank tests. Cox proportional hazard models will be used to explore association between covariates and outcomes.
次要结局
- Overall Response Rate After Retreatment With ICI With or Without CD24Fc After Resolution of irAE (Phase II)(Up to 1 year)
- Progression Free Survival (PFS) (Phase II)(From initiation of ICI to first documented evidence of disease progression or death, whichever comes first, assessed up to 1 year)
- Overall Survival (OS) (Phase II)(From start of treatment to death, assessed up to 1 year)
- Time to All irAEs Reduced to =< 1 From the Initiation of CD24Fc Treatment (Phase I)(Up to 2 weeks)
- Time to irAE Reduction by at Least 1 Grade From the Initiation of CD24Fc Treatment (Phase I)(Up to 1 year)
- Time to Resume Immune Check Point Inhibitor (ICI) Treatment From the Initiation of CD24Fc Treatment (Phase I)(Up to about 3.5 months)
- Recovery Rate (Reduction of irAE by One Grade) (Phase I)(At day 42)
- Time to All irAEs Reduced to =< 1 From the Initiation of CD24Fc Treatment (Phase II)(Up to 1 year)
- Use of Steroids and Other Drugs (Phase II)(Up to 1 year)
研究者
Tianhong Li
Principal Investigator
University of California, Davis